Intentional Rechallenge and the Clinical Management of Drug-Related Problems

Abstract

The use of medicines can lead to a wide variety of different problems. Taken together, drug-related problems are commonly encountered in medical practice and often therapeutic interventions of some sort are needed. Many such interventions may have a pragmatic or experimental side; established protocols are often not available. Prominent drug-related problems are adverse reactions, drug interactions and therapeutic failure [1]. In addition to drug discontinuation, a characteristic intervention associated with—often suspected—adverse drug reactions, is a re-exposure test: an intentional rechallenge. Such a re-exposure can, even in small amounts, be dangerous, however, and acute and fulminant reactions may occur. A rechallenge test may raise major clinical, scientific and ethical concerns. In life-threatening adverse reactions, such as toxic epidermal necrolysis, Stevens–Johnson Syndrome or agranulocytosis (Schultz disease), a rechallenge is almost always contraindicated. Sometimes a skin test or laboratory finding can help, such as a patch test, RAST (radioallergosorbent) test, a lymphocyte stimulation test or other evidence of drug-dependent immunity. On the other hand, refraining from a—careful and monitored—rechallenge test and the persistence of uncertainty may, in a different way, put a patient at serious risk. Some signs during the original adverse event may be predictive of a future serious response, e.g. urticaria, wheezing, angioedema (risk signs for a future anaphylactic reaction), eosinophilia, fever, abnormal liver tests (increased aminotransferase levels) or low blood counts. On the other hand, many other adverse drug effects are less serious and careful reintroduction of the drug, usually at a lower dose, may be safe, beneficial and satisfactory for the patient. Drug rechallenge and ‘dechallenge’, in the true sense of the words, are planned, prospective experiments, comparable with an ‘N-of-1 clinical trial’ [2]. The prime reason for a rechallenge is the acquisition of additional information as needed for the (future) treatment and well-being of the patient. Abandoning the future use of a drug or group of drugs, or therapeutic dilemmas when a treatment is urgently needed may be disastrous to the patient. For such reasons, further evidence regarding the likelihood of involvement of a suspected drug may be of substantial importance. In addition, rechallenge observations—when made available—may contribute to science and create further knowledge, and be of value to other (future) users of the drug, as well as to companies and regulators (and lawyers and judges). For many drugs and adverse reactions there is little or no information about the best way forward in the case of a rechallenge. For only a few drugs, for instance b-lactam antibiotics, there is a substantial body of published knowledge on how to proceed in suspected hypersensitivity. In a hospital setting, expertise may have accumulated in specialized units, for instance dermatology, clinical pharmacology or allergology.